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Get Your Wonder Drugs!: But do you know what it takes to produce them? - high costs of drug research and developmentHarry Howard almost made the biggest blunder of his life when he tossed the building blocks of a wonder drug

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Get Your Wonder Drugs!: But do you know what it takes to produce them? - high costs of drug research and development

Get Your Wonder Drugs!: But do you know what it takes to produce them? - high costs of drug research and developmentHarry Howard almost made the biggest blunder of his life when he tossed the building blocks of a wonder drug into a laboratory trash bag 14 years ago. He had just created a new molecule at Pfizer's research building in Groton, Conn.-a molecule that had never existed before and that, he hoped, might eventually prove useful in treating schizophrenia. After running a test on it, Howard poured the contents of a test tube through a filter and into a flask. Then he threw out the filter and examined the liquid left behind. It didn't seem to have any of the properties he had expected. Oh well, he thought, chemicals can do weird things.

The next day, however, it occurred to him that perhaps he was looking in the wrong place. "It's a good thing I hadn't taken the trash out," he says, "because my compound was stuck in that filter."

Over the course of the next decade, Pfizer would invest hundreds of millions of dollars in what Howard yanked from the trash. Today, his compound is called Geodon. It went on the market almost two years ago and, by most accounts, it's one of the best medications available to people with schizophrenia. Pfizer won't say exactly how much money it poured into Geodon, but one estimate says a successful drug can require an investment of $800 million before the Food and Drug Administration will approve it. There are thousands of failures for every success-and somehow Pfizer must pay for them as well.

In a good year, Pfizer might win approval for one or two brand-new products. It then has only a short time to earn back what it has invested. Geodon's patent, for instance, expires in March 2007, at which point generic copies will begin to flood the pharmacy shelves. By then, Pfizer will have had just six years to pay for the huge costs that went into making Geodon. The company estimates that it spends $100 million on research and development per week. Within the next five years, it will lose the patents for four of its eight most popular drugs.

Everybody loves wonder drugs, but nobody seems to want to pay for them. One industry-sponsored poll revealed that 90 percent of Americans believe the price of prescription drugs is a "major problem" and 60 percent support outright price controls. Few people appreciate that innovation doesn't come cheap, especially when drugs must pass through expensive regulatory hurdles meant to test their safety and effectiveness. Wonder drugs may seem like miracles, but they don't rain down upon us like manna. Producing even one requires a monumental effort.

Perhaps nothing can illustrate this point better than a story, and Geodon's story begins with the problem of schizophrenia. "It's one of the worst mental diseases out there," says Steven Romano, a Pfizer psychiatrist. Schizophrenics suffer from hallucinations, delusions, and social withdrawal, among other symptoms. Some 2 million Americans have the disease, and many of them can't hold down a regular job: John Nash, the Princeton mathematician portrayed by Russell Crowe in the movie A Beautiful Mind, may be this country's best-known schizophrenic. "It has exacerbations and remissions, but it's chronic-it's always there, and there's no cure," says Romano.

The earliest drugs for schizophrenia could control the hallucinations and delusions, but only at the cost of grisly side effects, such as severe muscular tremors. During the 1970s and 1980s, scientists began looking for alternatives, and Geodon had its origins in this broad effort. By the early 1990s, new products that didn't make muscles go haywire were on the market, but these had their own downsides, such as sharp weight gain. As a result, many schizophrenics were getting their main symptoms under control, only to quit their meds because they didn't like the side effects.

Harry Howard was one of several Pfizer employees in the 1980s charged with producing compounds that might improve the treatment of schizophrenics. "Discovery" scientists like Howard spend their days assembling molecules that have never existed before and then seeing how they behave in test tubes. "This part of the process is all about creativity," says Stevin Zorn, who led much of the Geodon research. "There's no cookbook on how to make a successful compound. It's art as much as science."

It's also drudgery. Even after Howard had constructed the original Geodon molecule-code-named CP88059-his creation faced long odds. "For every 150,000 compounds our scientists create, we figure one of them will make it to the marketplace," says Derek Leishman, a pharmacologist with Pfizer in England. It's so rare for a compound to make it to the shelves, in fact, that many discovery scientists will spend their entire careers working on compounds that never become approved drugs.

When a compound looks promising in the test tubes, Pfizer scientists begin putting it into animals-mostly mice, rats, and dogs. They want to make sure their proto-drug isn't toxic. They're also looking for clues about how it might act in humans. With CP88059, scientists were hoping to spot muscle rigidity, a negative side effect that had been associated with other successful antipsychotic medications. But they found nothing of the sort, which suggested that CP88059 might be a different breed of drug. By this point, in 1989, it was time for Geodon to "get canned."

This is an important milestone, as a compound moves from one side of the R&D ampersand to the other. It's called "getting canned" because the company puts out a "Candidate Alert Notice" (CAN)-basically an all- points bulletin announcing that the drug has cleared its first set of obstacles. Yet the most challenging phase still lies ahead: Fewer than 10 percent of canned compounds ever make it to the marketplace.

The discovery scientists had produced a fine, white powder that looked similar to flour. But one of the great predicaments companies like Pfizer face consists in moving from the pure science of compound creation to the applied science of developing a form of the drug that patients can use, such as a pill or capsule. The final product must be able to survive on the shelf for a couple of years, remain stable in hot and cold temperatures, and deliver enough punch in a single dose that patients won't have to pop pills a dozen times a day.

This step is harder than it sounds, but it's essential to the pharmaceutical business-and it's in this area that Pfizer made its first great contribution to humanity. In 1928, Alexander Fleming found that a common airborne mold known as penicillium could vanquish pneumonia and scarlet fever-but only in a petri dish. He had enormous trouble preserving the mold's active substance. It wasn't until the Second World War that anybody was able to produce penicillin in a useful form. Pfizer was the company that figured out how to do it.

Pfizer faced this same challenge with Geodon-converting a known substance into a product people could actually use. "It took us two years to learn how to get it into patients, and then a few more years of optimizing," says Bijan Rasadi, one of Pfizer's chief pharmaceutical scientists. The entire development process took nine years.

A canned compound eventually graduates to clinical testing, when it's put into humans for the first time. The first phase of Geodon's clinical trials began in 1991 and, as first phases always do, it involved a few dozen healthy subjects-non-schizophrenics who were willing to serve as human guinea pigs. The point of these initial tests isn't to see whether a drug works, but to determine whether it's safe for human consumption. "Geodon's first phase was uneventful," says Rachel Swift, Pfizer's executive director of clinical development. That was precisely the news she wanted to hear.

Once a drug's safety has been established in Phase One, scientists next examine its efficacy. These Phase Two trials typically involve several hundred people affected by the problem the drug is supposed to address. Researchers are generally confident that their drug will have some effect, but they need to determine ideal dosage levels.

Geodon's Phase Two trials were also uneventful-perhaps a bit too much so. Pfizer's R&D scientists saw that Geodon was helping patients, but it didn't outperform existing medications. If Geodon were ever to make it to the marketplace, it would require yet more investment, and at the end of the process there still had to be a reasonable hope that it would generate revenue. A redundant drug wouldn't. There was a strong case for putting the brakes on Geodon. This is a fairly common occurrence even for drugs that enter the second phase of clinical testing.

Yet Pfizer was also hearing from doctors involved in the trials that compliance was up. Geodon patients weren't putting on the kind of weight associated with other treatments. If this drug were able to delete that side effect, the researchers thought, then perhaps they really had something.